Neurodegenerative diseases encompass a variety of disorders characterized by synaptic dysfunction, associated with a progressive decline in cognitive and functional abilities, often resulting in death. Alzheimer's disease (AD) is the most common age-associated debilitating neurodegenerative disorder, affecting approximately 4 million Americans and about 20-30 million people worldwide. The classical neuropathological features of AD include the presence of senile (β-amyloid-containing) plaques and neurofibrillary tangles in the hippocampus, the amygdala, and the association cortices of the temporal, frontal and parietal lobes. More subtle changes include reactive astrocytic changes, as well as the loss of neurons and synapses in the entorhinal cortex and basal forebrain.
The pathogenesis of Alzheimer's Disease is not fully understood, however it is known that there is an association between the disease and a cleavage product of the membrane protein, Amyloid Precursor Protein (APP). γ-secretase mediates the C-terminal cleavage of the amyloid-β (Aβ) domain of APP, thereby liberating Aβ/p3 from membrane-bound APP C-terminal fragments generated through ectodomain shedding by α-(ADAM10 and TACE) or β-secretase (BACE1). γ-secretase cleavage generates two major Aβ isoforms—Aβ40 and Aβ42. It has been well documented that all mutations in presenilin genes PS1 and PS2 result in modulation of γ-secretase activity, leading to an elevation in the generation of the highly amyloidogenic and neurotoxic Aβ42 species, possibly at the expense of the more benign Aβ40 peptide.
Phosphoinositides (“PIs”) serve as signaling molecules in a diverse array of cellular pathways (Williams, 1999, Biochim. Biophys. Acta 1441: 255-267; Rhee and Bai, 1997, J. Biol. Chem. 272(24): 15045-15048; Katan, 1998. Biochim. Biophys. Acta 1436: 5-17) and aberrant regulation of PIs in certain cell types has been shown to promote various human disease states (Pendaries et al., 2003, FEBS Lett. 546(1):25-31 PI signaling is tightly regulated by a number of kinases, phosphatases, and phospholipases. The hydrolysis of phosphotidylinositol 4,5-biphosphate (PIP2) by phospholipase C(PLC) is an early and key event in the regulation of a variety of cell functions. It has been discovered that Aβ42 causes a decrease in PIP2 levels (see International Patent Application No. PCT/US2007/085274, WO 2008/064244, incorporated by reference herein).
Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine to form phosphatidic acid (see International Patent Application No. PCT/US2007/085274, WO 2008/064244, incorporated by reference herein; Sweeney et al., 2002, J. Biol. Chem. 277:3030-3039; Exton et al., 2002, FEBS Lett 531:58-61; Schields and Aryan, 1999, Curr. Opin. Cell Biol. 11:489-494). PLD has been reported to regulate various membrane trafficking steps (e.g., the release of secretory vesicles, endocytosis and exocytosis (Chen et al., 1997, J. Cell Biol. 138:495-504; Shen et al., 2001, Mol. Cell. Biol. 21:595-602; Humeau et al., 2001, Proc. Natl. Acad. Sci. 98:15300-'5305; Cockcroft, 2001, Cell. Nol. Life Sci. 58:1674-1687). PLD1 and PLD2 are two different isoforms of this enzyme (Hammond et al., 1995, J. Biol. Chem. 270:29640; Colley et al., 1997, Curr. Biol. 7:191; Steed et al., 1998, FASEB J. 12:1309; see FIG. 1A-B) and are reported to have different cellular functions (Choi et al., 2002, J. Immunol. 168:5682-5689). Cai et al., 2006, Proc. Natl. Acad. Sci. U.S.A. reports that PLD1 regulates intracellular trafficking of βAPP and its companion paper (Cai et al., 2006, Proc. Natl. Acad. Sci. U.S.A. 103:1941-1946) reports that through an independent mechanism PLD1 compromises the integrity of the γ secretase complex, inhibiting β-amyloid formation. Cai et al suggest that defects in PLD metabolism may contribute to Alzheimer's Disease pathogenesis.